1. Field of the Invention
The present invention relates to an agent for suppressing growth of the vascular endothelial and an inhibitor of angiogenesis induced by growth of the vascular endothelial cells which comprises Tissue Factor Pathway Inhibitor (TFPI) as active ingredient. More particularly, the present invention relates to a TFPI-containing preparation for prevention and treatment of angiogenic diseases through effective inhibition of angiogenesis induced by growth of the vascular endothelial cells.
2. Description of the Related
Angiogenesis is growth of new blood vessels, especially capillary vessels. Although angiogenesis is a significant physiological event for developing embryos or growing individuals, it is widely known that angiogenesis mostly detrimentally affects healthy adults and is only favorable to healing of wounds or menstrual cycle. In case of malignant tumors, for example, growth of the vascular endothelial cells or angiogenesis of capillary vessels is essential to development of tumor tissue. It is considered this is because the tumor cells produce and secrete a growth factor necessary for angiogenesis, and as a result, the vascular endothelial cells are stimulated to divide and propagate towards the tumor site. Accordingly, inhibition of angiogenesis can be a means to control growth of malignant tumors.
For treating malignant tumors, surgical enucleation of the tumors has been conducted. However, if any one of tumor cells fails to be removed but remains in the affected part after enucleation of the tumors, relapse of the tumor occurs. Moreover, it is reported that tumor cells appearing in blood flow increase during or after surgical nucleation of tumor tissue where angiogenesis is highly developed, implicating an increased risk of metastasis to other organs [McCulloch, P. et al., The Lancet, 346, p1334 (1995)]. In case of such a surgical enucleation of tumor tissue, the use of an angiogenic inhibitor that can inhibit angiogenesis will permit prevention of relapse at the primary focus and growth of metastasized tumor cells and hence can be a means for treating malignant tumors.
In addition to propagation of malignant tumors, there are known various diseases induced by angiogenesis, including the so-called angiogenic diseases such as diabetic retinopathy, retrolental fibroplasia, neovascular glaucoma, psoriasis, angiofibroma, immune and nonimmune inflammation (including rheumatic arthritis), propagation of capillary vessels in arteriosclerosis plaques, angioma and Kaposi's sarcoma [Folkman, J. et al., Science, 235, p442 (1987)]. One can well expect that inhibition of angiogenesis could treat these diseases.
It has been confirmed that the growth of endothelial cells of blood vessel is much significant in the mechanism of angiogenesis. That is, angiogenesis occurs in the following mechanism: (i) the basement membrane of the existing blood vessels is first degraded by the action of a proteolytic enzyme and then the endothelial cells are released out of the locally destroyed membrane, (ii) the released endothelial cells migrate into the extravascular area where they proliferate through cell division, (iii) after the proliferation, they gradually differentiate into the tube-like structure and a new blood vessel is then formed, and (iv) finally the new blood vessel is combined together to complete angiogenesis [Folkman, J. et al., J.Biol.Chem., 267, p10931 (1992)]. As a promoting factor of angiogenesis, there are known peptidic substances, acidic Fibroblast Growth Factor (aFGF) and basic Fibroblast Growth Factor (bFGF), which induce angiogenesis through acceleration of release and growth of the vascular endothelial cells. Recently, a vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), which is a growth factor specific for the vascular endothelial cells, was found as a new promoting factor of angiogenesis [Ferrara, N. et al., J.Clin.Invest., 84, p1470 (1989)].
There are known several compounds that exhibit inhibition against growth of the vascular endothelial cells. Among them is protamine, which is a protein of a molecular weight 4,300 that occurs only in sperm and is abundant in a basic amino acid arginine. The hitherto experiments confirmed that protamine inhibits growth of tumors through inhibition of angiogenesis of tumors based on its heparin-binding ability [Taylor, S. et al., Nature, 297, p307 (1982)]. However, protamine is known to be antigenic in humans and to induce anaphylactic reaction on and after the second administration. Due to this toxicity, it is difficult to frequently use protamine in humans. Accordingly, there have been vastly investigated substances that are effective as an inhibitor of growth of the vascular endothelial cells and angiogenesis but are not toxic in humans. However, at present, compounds that exhibit both the effective activity to inhibit angiogenesis and safety in humans have not yet been found.